This program project investigates the role that various sensory receptors (mechanical and chemical) play in the control of breathing. State-of-the-art neurophysiological, neuropharmacological, immunohistochemical and neuroanatomical techniques will be employed to define selective inputs to the respiratory control system with respect to their characteristics and overall influence in shaping the respiratory motor drive and to some extent lung mechanics. Project 1 will isolate and class. By individual diaphragm sensory receptors and determine if they are activated during normal and/or manipulated (mechanically, chemically) breaths. Project 2f will record respiratory-related evoked responses (sensory and motor) to determine, in human subjects the involvement of diaphragmatic afferents in the perception of added loads to breathing. In project 3, a chronic- dog model will be utilized to investigate the role of vagal afferents (bronchopulmonary receptors) in the reflex response to inhaled irritants (cigarette smoke, etc.). The brainstem site(s) where reflex effects are mediated will be investigated in Project 4 by conducting systematic microlesion experiments in selected nuclei. Neuroanatomical techniques (anterograde tracing, retrograde tracing, immunohistochemistry) will be employed in Project 5 to investigate the nature of the synaptic connection(s) and neurotransmitters of phrenic and intercostal nerve afferents. Project 6 will utilize an in vitro brainstem slice preparation to examine the pharmacological effects of putative neuro-transmitters on specific cell types within the dorsal respiratory group. project 7 will investigate the role of axon reflexes in the regulation of airway hyperreactivity. The various types of nerve fibers and their pharmacological mechanisms will be the central focus. With this multi-faceted approach peripheral receptor activity in response to perturbations can be characterized, traced into the central nervous system, the central connections and interactions described and finally, the effect on respiratory motor output determined. The development of this interdisciplinary program project is a natural out-growth of the long standing interaction among members of the respiratory group at the University of Kentucky. It will provide both basic and clinically relevant information concerning the control of breathing.